Stent Coating For Eluting Medication

ABSTRACT

A vascular stent comprising a drug-eluting outer layer of a porous sputtered columnar metal having each column capped with a biocompatible carbon-containing material is described. This is done by placing the stent over a close-fitting mandrel and rotating the assembly in a sputter flux. The result is a coating that is evenly distributed over the outward-facing side of the stent&#39;s wire mesh while preventing the sputtered columnar coating from reaching the inward facing side where a smooth hemocompatible surface is required. The stent is then removed from the mandrel, exposing all surfaces, and finally coated with a layer of carbon such as amorphous carbon or diamond-like carbon. The carbonaceous coating enhances biocompatibility without preventing elutriation of a therapeutic drug provided in the porosity formed between the columnar structures. The result is a stent that is adapted to both the hemodynamic and the immune response requirements of its vascular environment.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.11/307,226, filed Jan. 27, 2006.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to stents provided with coatings for elutingmedication to prevent or lessen the severity of restenosis.

2. Prior Art

In order to minimize the response of surrounding tissue to the trauma ofstent insertion and expansion, stent coatings must be biocompatible. Afurther requirement is that a stent coating must adhere to a substrateundergoing plastic deformation. This occurs during insertion andexpansion of the stent into the vasculature system. Plastic deformationinvolves grain rotation and elongation, and intersection of slip planeswith the substrate surface. The result is that on a scale below thegrain size of the substrate, deformation is highly non-uniform, withsome areas undergoing little or no deformation and others extremedeformation with associated increase in surface roughness andirregularity. Therefore, coating adhesion must be preserved through thedeformation process.

Conventional stent coatings can be classified as being either passive oractive. Passive coatings rely on biocompatible materials to minimize thebody's response to placement of the stent into the vasculature.Generally recognized “passive” coating materials include carbon, iridiumoxide, titanium, and the like, as disclosed in U.S. Pat. No. 5,824,056to Rosenberg. U.S. Pat. No. 5,649,951 to Davidson discloses coatings ofzirconium oxide or zirconium nitride.

Drug eluting or “active” coatings have proven more effective for theprevention of restenosis. Such stents generally comprise a surfacepolymer containing a therapeutic drug for timed release. A secondcoating may be added to extend the period of effectiveness by limitingthe rate of drug diffusion from the first, drug-containing coating. Thissecond coating may be a polymer, or a sputtered coating as described inU.S. Patent No. to 6,716,444 to Castro et al.

However, polymeric drug eluting coatings suffer from a number ofdisadvantages. First, they can have poor adhesion to the stent,especially while undergoing plastic deformation during insertion andexpansion of the stent into the vasculature. Secondly, due tobiocompatibility/hemocompatibility issues some polymers actuallycontribute to restenosis. Finally, that part of the coating facing theinside of the vasculature lumen loses its medication content to thebloodstream with little beneficial effect.

U.S. Pat. No. 6,805,898 to Wu et al. attempted to overcome adhesionproblems by introducing roughness to the vasculature-facing portion ofthe stent while leaving the blood-facing side in a polished conditionfor better hemocompatibility. Surface roughness was increased by meansof grit blasting, sputtering, and the like. Not only did augmentingsurface roughness improve adhesion between the polymer and the stent, italso allowed for a thicker polymer coating to be applied. However, thefinal stent configuration still had eluting polymer in contact with bodytissue, allowing biocompatibility issues to persist.

U.S. Pat. No. 5,607,463 to Schwartz et al. carried out experiments inwhich it was shown that tissue response to polymers could be reduced bymeans of a barrier layer of tantalum and niobium thin films on theexposed polymer surfaces. Specifically, in vivo tests showed an absenceof thrombosis, inflammatory response, or neointimal proliferation when athin tantalum or niobium barrier layer covered a polymer. However, inthe case of a drug eluting polymer, these coatings detrimentallyisolated the drug from the tissue as well.

U.S. Patent Application Pub. No. 2004/0172124 to Vallana et al.optimized the coating configuration by limiting the drug-elutingmaterial to only that portion of the stent surface in contact with thevasculature. This was done by confining the drug eluting polymer tooutward facing channels which were micro-machined into the stent meshelements. All other stent surfaces were coated with hemocompatiblecarbon. Thus, the use of a biocompatible-problematic carrier polymer wasminimized, but not eliminated.

In addition, U.S. Pat. No. 6,820,676 to Palmaz shows that, independentof the stent's surface composition, the surface texture of the stent orcoating has an effect on the ability of proteins to adsorb into thestent surface, ultimately allowing thrombosis formation. It was shownthat the surface texture can be controlled by grain size and other meansto prevent protein adsorption and subsequent thrombosis.

Thus, even though much work has been done to develop stent systemscomprising drug eluting polymers while minimizing, and even eliminating,thrombosis, inflammatory response and neointimal proliferation, furtherimprovements are required to fully realize these goals. The presentstent coating is believed to accomplish just that.

SUMMARY OF THE INVENTION

In the present invention, the drug-eluting outer layer of a stentconsists of a porous sputtered metal or ceramic coating rather than aconventionally deposited polymer. This is done by placing the stent overa close-fitting mandrel and rotating the assembly in a sputter flux. Theresult is a coating that is evenly distributed over the outward-facingside of the stent's wire mesh while preventing the sputtered coatingfrom reaching the inward facing side where a smooth hemocompatiblesurface is required. The stent is then removed from its mandrel,exposing all surfaces, and finally coated with a layer of carbon such asamorphous carbon or diamond-like carbon. The carbonaceous coatingenhances biocompatibility without preventing elution of the therapeuticdrug. The result is a stent that is adapted to both the hemodynamic andthe immune response requirements of its vascular environment.

These and other objects and advantages of the present invention willbecome increasingly more apparent by a reading of the followingdescription in conjunction with the appended drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a stent 12 supporting a blood vessel10 according to the present invention.

FIG. 2 is a cross-sectional view of a wire 14 comprising the stent 12shown in FIG. 1.

FIG. 2A is an enlarged cross-sectional view of the indicated portion ofthe stent wire 14 shown in FIG. 2 comprising a biocompatible porouscolumnar coating 16 supported on the stent wire 14 with a thincarbonaceous material 18 providing a cap on each of the columns as wellas covering the inside-facing surface 14B of the wire.

FIG. 3 is a cross-sectional view of the stent portion shown in FIG. 2A,but with the capillary spaces between the columnar coating 16 infusedwith a medication compound 20.

FIG. 3A is an enlarged cross-sectional view of the indicated portion ofFIG. 3.

FIG. 4 is a cross-sectional view showing the interface between the stentand blood vessel 10 after deployment of the stent 12.

FIG. 5 is an SEM photograph of a fracture cross-section of a porouscolumnar titanium nitride coating with porous carbon caps.

FIG. 6 is a SEM photograph showing sputtered columnar aluminum nitrideadhering to a substrate that has been subjected to plastic deformation.

FIG. 7A is a schematic view of an unstrained stent wire 14 in a zerostress state.

FIG. 7B is a schematic view of the stent'wire 14 shown in FIG. 7A havingbeen strained within its elastic limit and depicting the resultingtension and compression stress forces therein.

FIG. 7C is a schematic view of the stent wire 14 shown in FIG. 7B beingelastically strained and provided with a columnar coating 16 that is anunstrained state.

FIG. 7D is a schematic view of the stent wire 14 shown in FIG. 7C in arelaxed, unstrained state and depicting the resulting tension andcompression stress forces in the columnar coating 16.

FIG. 7E is a schematic view of the stent wire 14 shown in FIG. 7C havingbeen expanded past its elastic limit and depicting the resulting tensionand compression stress forces in both the wire and the columnar coating16.

FIG. 8A is a cross-sectional view of a polymer 26 used as a reinforcingmaterial between individual columns 16.

FIG. 8B is a cross-sectional view of the stent shown in FIG. 8A providedwith a diffusion limiting polymeric coating 28.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has been found that coatings having a columnar structure can be madeto adhere strongly to a substrate even while the substrate undergoesextensive plastic deformation. This is possible because the porous filmconsists of many strongly adhering individual columns rather than asingle thin film coating. Furthermore, it has been shown that when thincolumnar coatings are themselves coated with a biocompatible materialsuch as carbon, the carbon continues the original columnar structurerather than disposing itself as a continuous non-porous barrier layer.This is described in U.S. Patent Application Pub. No. 2004/0176828 toO'Brien, which publication is assigned to the assignee of the presentinvention and incorporated herein by reference. These characteristicsare put to use in the present invention as a medication-carryingstructure on a stent for the purpose of eluting the medication intosurrounding tissue to lessen or prevent restenosis.

Referring now to the drawings, FIG. 1 shows a cross-section of a bloodvessel 10 with a stent 12 inserted and expanded therein. In the currentinvention, the medication eluting coating is limited to that portion ofthe stent in contact with tissue, which is exemplified by the bloodvessel 10.

The stent 12 is comprised of a plurality of wires 14 forming anelongated hollow tube and disposed so as to be capable ofcircumferential expansion. Commonly used stent materials includeplatinum, Nitinol, and even medical grade 316L stainless steelcontaining about 16% nickel. The wires 14 provide for an elongated,expandable hollow tube that can, in a preferred embodiment, increase indiameter when the ends of the hollow tube are moved closer relative toeach other and decrease in diameter when the ends are moved apart. Adesign objective is to have as little length change as possible when thestent is expanded. Physicians have a hard enough time lining up a stentwith a lesion without it acting like an accordion.

The stent 12 is positioned in the vasculature of a patient during orafter a procedure, such as an angioplasty, atherectomy, or otherinterventional therapy, and then expanded to an appropriate size (i.e.,approximately the same diameter as the vessel 10 in the region whereplaced), thus supporting that vascular region. When in its expandedconfiguration, the stent 12 provides support to the vascular wallsthereby preventing constriction of the vascular region in which it islocated and maintaining the vascular lumen open. This is often referredto as maintaining vascular patency.

FIG. 2 represents a cross-section of a wire 14 comprising the vascularstent 12. The stent wire 14 has a roughly circular cross-sectioncomprising an outside-facing surface 14A and an inside-facing surface14B. The outside-facing surface 14A of the stent wire faces the bloodvessel wall and serves as a substrate provided with a coating 16 ofcolumnar material to a thickness of about 0.1 μm to about 20 μm.Sputtering causes the columnar material to first be physically absorbedwith some implantation into the wire material. This is due to thekinetic energy generated by the sputtering process prior to the columngrowing to its desired length.

While sputtering is a preferred method for depositing the columnarcoating 16, other suitable thin film deposition method can be used.These include chemical vapor deposition, pulsed laser deposition,evaporation including reactive evaporation, and thermal spray methods.Also, while the wire 14 is shown having a circular cross-section, thatis not necessary. Other embodiments of the stent 12 comprise wires 14having triangular, square, rectangular, hexagonal, and the likecross-sections.

As shown in FIGS. 3 and 3A, each column of the coating 16 comprises anintermediate portion 16A extending to a base 16B adhered to theinside-facing surface 14B of the wire 14 and a tip 16C. Each column isof a relatively consistent cross-section along its length extending tothe base 16B and tip 16C. That way, the columns are discrete membersthat only adhere to the wire substrate at their base 16B, but do notjoin to an immediately adjacent column. Titanium nitride is a preferredmaterial for the columnar coating 16, although other useful materialsinclude, but are not limited to, boron, aluminum, calcium, gold,hafnium, iridium, molybdenum, niobium, platinum, rhenium, ruthenium,silicon, silver, tantalum, titanium, tungsten, yttrium, and zirconium,and carbides, oxides, nitrides, oxynitrides, carbonitrides thereof.

To further lessen the response of contacted tissue to the presence ofthe stent 12, the inside-facing surface 14B of the wire 14 as well aseach columnar tip 16C is coated with a carbonaceous material 18, such asamorphous carbon or diamond-like carbon. During this operation, thecarbon 18 assumes the morphology of a “cap” adhered to each tip 16C ofthe porous columnar coating 16 supported on the outside-facing surface14A of the stent wire 14. The carbon caps 18, which are also preferablyprovided by a sputtering process, are at a thickness of about 0.05 μm toabout 2.0 μm. That is, the porosity of the drug-eluting columnar coating16 is maintained. This is because while the thickness of the carbon capis sufficient to impart biocompatibility to the columnar tip 16C, it isinsufficient to form a continuous coating that could detrimentallyisolate the drug eluting porosity inherent in the columnar structure.The carbon 18 that coats the bare metal inside-facing surface 14B of thestent wire 14 forms a smooth continuous pore-free layer suitable forcontact with blood.

Finally, as shown in FIGS. 3 and 3A, the capillary spaces between thecolumns of the coating 16 and the carbon cap 18 are infused withmedication 20 to inhibit restenosis. This can be done by various methodswell known to those skilled in the art including spraying the stent witha medication solution, dipping the stent into a medication solution,immersing the stent in a medication solution under vacuum conditions andcentrifuging the medication solution into the porosity.

FIG. 4 shows the interface between the treated stent wire 14 and theblood vessel 10 after deployment of the stent 12 therein. Medication 20residing in the capillary spaces of the columnar coating 16 is directedinto the vessel 10 supported by the stent with the vessel tissue onlycontacting the biocompatible carbonaceous caps 18.

It is to be appreciated that the schematics of FIGS. 1 to 4 do notillustrate the extremely high surface area present in the inter-columnarcapillaries. FIG. 5 is a SEM photograph of a fracture cross-section of aporous columnar coating illustrating the volume of empty space thereinand the internal surface roughness of the capillaries. In this case, theporous columnar coating consists of titanium nitride, which is widelyused as a permanent implantable coating for bioelectrodes. Also visiblein the photograph is the carbon cap on each individual titanium nitridecolumn, comprising the outer 200 nm to 300 nm of the coating. Depositionof the carbon layer was done with the mandrel removed from the stentmesh. The mesh was fixtured to expose all surfaces of the stent tosputter flux. The stent was rotated in the sputter flux duringdeposition, which was done with DC sputtering of a carbon target inargon process gas. Typical conditions are 7 mTorr, 250 Watts, no bias.The result is a stent that presents a relatively thick, porous elutinglayer containing therapeutic medication to the blood vessel wall, whilepresenting a smooth, hemocompatible face to the flowing blood.

FIG. 6 illustrates adhesion of a porous columnar coating of aluminumnitride even after extensive plastic deformation of the substrate.Reactive DC sputtering was used. The process gas was pure nitrogen at apressure of about 5.3 mTorr. Power was set at 250 W on a 3 inch diameterplanar target with no bias. Deposition time was 4 hours.

In that respect, a further aspect of the invention relates tocontrolling the stress state of each column comprising the coating 16supported on the stent wires 14. Fixturing the stent 12 on a mandrel(not shown) subjected to a sputter flux provides for coating theoutside-facing surface 14A thereof with the columnar coating 16 whileprotecting the inside-facing surface 14B of the stent wire 14.Increasing the degree of expansion over the mandrel to higher levels,within the elastic limit of the stent wire 14, and sputtering in thatexpanded state, lessens the overall stress on the columnar coating 16when the stent 12 is finally inserted and expanded in the blood vessel10. Then, when the stent is plastically deformed upon deployment intothe vasculature, the individual columns are less likely to delaminatefrom the wire substrate as their connection to the substrate is in arelatively less stressed state. The associated carbon caps 16 experiencethe same compression and tension stress forces because they essentially“ride” on the tips 16B of each column. This is illustrated in FIGS. 7Ato 7E.

FIG. 7A shows an unstrained stent wire 14. The wire has a generallyelongate U-shape comprising spaced apart struts 14C and 14D joinedtogether by a union portion 14E. Datum points 22 and 24 are indicatedadjacent to the terminus of the respective struts 14C, 14D. In actualitythe struts comprise a continuous structure such as a mesh and have no“terminus”. When the stent is placed over a supporting mandrel (notshown), the distance between the datum points 22, 24 is increased, asindicated by the opposing directions of the respective vector arrows 22Aand 24A in FIG. 7B. The stresses set up in the union portion 14E includeboth tension forces (+σ_(e)) and compression forces (−σ_(e)) within theelastic limits of the wire. The goal is to stress the union portion 14Eof the wire 14 within its elastic limits so that the tension andcompression strains create an opposite elastic pre-strain in the coatingwhen the stent is removed from the mandrel. The struts 14C, 14D remainrelatively unstressed.

FIG. 7C shows the stent wire 14 in the same stressed state illustratedin FIG. 7B, but after the sputtered columnar coating 16 is applied. Thecolumnar coating 16 is in a zero stress state. Then, as shown in FIG.7D, when the stent is removed from the mandrel, it elastically springsback with the distance between the datum points 22, 24 being at or nearto their original spacing shown in FIG. 7A. The columnar coating 16 isnow in a stressed state opposite to that shown for the substrate in FIG.7C. In that respect, the columnar coating 16 on the outside-facingsurface 14A is in a tension state within the elastic limits of the wirecoating material (+σ_(e)) while the columnar coating on theinside-facing surface 14B is in a compression state (−σ_(e)).

In FIG. 7E, the wire 14 undergoes plastic deformation during the stent'sexpansion and placement in the vasculature. This is depicted by theopposing directions of the respective vector arrows 22A, 24A. In thisfinal state, the stress in the coating 16 is the stress due todeformation of the wire surface at the union portion 14E minus thecoating pre-stress, as shown in FIG. 7E. Therefore, the final tension(−σ_(f)) and compression (+σ_(f)) forces in the coating 16 are somewhatless than they would have been had the columnar coating been provided onthe stent wire in a completely relaxed state in comparison to the actualstressed state the union portion 14E was in during the depositionprocess. The difference is the amount of elastic deformation in theunion portion 14E of the stent wire 14 while the coating was beingdeposited (FIG. 7C).

The elastic limit of the stent wire 14 can be determined by placing thestent over increasingly larger diameter mandrels, until the spring backupon removal does not return the stent to its original dimension.Alternately, the film pre-stress can be achieved by using a nickeltitanium shape memory alloy which can be made to assume the partiallyexpanded configuration by heating in the sputter chamber.

Another aspect of the invention is shown in FIG. 8A. This embodimentrelates to the use of a polymer 26 that is provided with a medicationand infused into the porous columnar coating 16 to improvebiocompatibility while increasing coating strength and adhesion.Suitable polymers include (but are not limited to) polyurethane,silicone, polyesters, polycarbonate, polyethylene, polyvinyl chloride,polypropylene methylacrylate, para-xylylene.

As shown in FIG. 8B, a polymer 28 can also be used to moderate andcontrol the diffusion of the medication from the capillaries of theporous coating 16 into the surrounding tissue. In that case thepolymeric coating 28 is added to the porous layer after it is infusedwith the therapeutic medication.

Because the process coats all surfaces of the stent, it allows selectionfrom a wider range of substrate materials, including those whichimproved radiopacity characteristics.

This is an important consideration for locating the stent correctlyduring placement in the vasculature.

It is appreciated that various modifications to the invention conceptsdescribed herein may be apparent to those of ordinary skill in the artwithout departing from the scope of the present invention as defined bythe appended claims.

1. A stent for insertion and expansion in a vasculature to support itsadjacent vasculature region, the stent comprising: a) a plurality ofwires forming an elongated and selectively expandable and constrictablehollow tube, each wire providing a substrate having a cross-sectioncomprising an outside-facing surface portion and an inside-facingsurface portion facing a lumen formed by the hollow tube; b) anintermediate coating adhered to the outside-facing surface portion ofeach substrate wire and comprising a plurality of columnar structureshaving a sidewall extending between a proximal end adhered to thesubstrate and a distal end spaced therefrom, wherein the sidewalls ofimmediately adjacent columns do not contact each other to therebyprovide porosity there between; c) a cap of a carbon-containing materialprovided on the distal end of each of the plurality of columnarstructures; and d) wherein the porosity provided between each of theplurality of columnar structures is adapted for receiving an elutablematerial therein.
 2. The stent of claim 1 wherein the carbon-containingmaterial provides a thin film on the inside-facing surface portion ofthe wire substrate.
 3. The stent of claim 1 wherein the intermediatecoating is selected from the group consisting of carbides, oxides,nitrides, oxynitrides, and carbonitrides of titanium, boron, aluminum,calcium, gold, hafnium, iridium, molybdenum, niobium, platinum, rhenium,ruthenium, silicon, silver, tantalum, titanium, tungsten, yttrium,zirconium.
 4. The stent of claim 1 wherein the carbon-containing coatingis selected from an amorphous carbon and a diamond-like carbon.
 5. Thestent of claim 1 wherein the intermediate coating is adhered to thesubstrate and the carbon-containing coating is provided as the cap onthe distal end of each of the plurality of columnar structures by one ofthe deposition techniques selected from the group consisting ofsputtering, chemical vapor deposition, pulsed laser deposition, reactiveevaporation, and as a thermal spray.
 6. The stent of claim 1 wherein theplurality of columnar structures comprising the intermediate coatingeach have a length of about 0.1 μm to about 20 μm.
 7. The stent of claim1 wherein the carbon-containing coating has a thickness of about 0.05 μmto about 2.0 μm.
 8. A method for providing a stent suitable forinsertion and expansion into a vasculature to support an adjacentvasculature region, comprising the steps of: a) providing a plurality ofwires forming an elongated and selectively expandable and constrictablehollow tube, each wire providing a substrate having a cross-sectioncomprising an outside-facing surface portion and an inside-facingsurface portion; b) adhering an intermediate coating to theoutside-facing surface portion of each substrate wire, the intermediatecoating comprising a plurality of columnar structures having a sidewallextending between a proximal end adhered to the substrate wire and adistal end spaced therefrom, wherein the sidewalls of immediatelyadjacent columns do not contact each other to thereby provide porositythere between; c) capping the distal end of each of the plurality ofcolumnar structures with a carbon-containing material; and d) filling anelutable material into the porosity provided between each of theplurality of columnar structures.
 9. The method of claim 8 includingexpanding the stent to near an elastic stress limit of the plurality ofwires prior to providing the intermediate coating thereon.
 10. Themethod of claim 8 including providing the stent comprising a nickeltitanium shape memory alloy heated to near an elastic stress limit ofthe plurality of wires prior to providing the intermediate coatingthereon.
 11. The method of claim 10 including heating the nickeltitanium shape memory alloy to near its elastic stress limit in asputter chamber.
 12. The method of claim 8 including providing theelutable material as a medication filled into the porosity between thecolumnar structures and comprising a polymer selected from the groupconsisting of polyurethane, silicone, polyesters, polycarbonate,polyethylene, polyvinyl chloride, polypropylene methylacrylate,para-xylylene, and mixtures thereof.
 13. The method of claim 8 includingproviding a polymeric material covering the carbonaceous caps.
 14. Themethod of claim 8 including adhering the intermediate coating to thesubstrate and capping the distal end of each of the plurality ofcolumnar structures with the carbon-containing coating by one of thedeposition techniques selected from the group consisting of sputtering,chemical vapor deposition, pulsed laser deposition, reactiveevaporation, and as a thermal spray.
 15. A method for providing a stentsuitable for insertion and expansion into a vasculature to support anadjacent vasculature region, comprising the steps of: a) providing aplurality of wires comprising a shape memory alloy forming an elongatedand selectively expandable and constrictable hollow tube, each wireproviding a substrate having a cross-section comprising anoutside-facing surface portion and an inside-facing surface portion; b)heating the shape memory alloy to near its elastic stress limit; c)adhering an intermediate coating on the outside-facing surface portionof each substrate wire, the intermediate coating comprising a pluralityof columnar structures having a sidewall extending between a proximalend adhered to the substrate wire and a distal end spaced therefrom,wherein the sidewalls of immediately adjacent columns do not contacteach other to thereby provide porosity there between; d) capping thedistal end of each of the plurality of columnar structures with acarbon-containing material formed thereon; and e) filling an elutablematerial into the porosity provided between each of the plurality ofcolumnar structures.
 16. The method of claim 15 including providing thestent comprising a nickel titanium shaped memory alloy.